The formation and deposition of amyloid fibrils is associated with more than 20 neurodegenerative diseases. These include Alzheimer's, Parkinson's, Huntington's diseases, and the transmissible spongiform encephalopathies and type II diabetes. Oligomeric or other prefibrillar precursors of the fibrils are believed to be the main toxic species, but the mechanism of cell and tissue damage in amyloid-related diseases is not well understood. Improvement of our knowledge of the structure, kinetics of amyloidogenic polypeptides, and of their toxicity is essential for the development of effective treatments of amyloid disorders. Coherent multidimensional optical techniques provide novel probes into the fibril fluctuating structure through the response of molecular vibrational and electronic motions to sequences of carefully timed and shaped femtosecond laser pulses ranging from the infrared to the ultraviolet. Simulation techniques aimed at the design and interpretation of these multidimensional optical signals will be developed. Chirality-induced signals obtained by optimizing the pulse polarization configurations and shapes enhance the resolution and reveal fine details. Cross-peak patterns between side-chain vibrations or electronic excitations of aromatic side-chains with the protein backbone protein/membrane interfaces will be predicted in two-dimensional (2D) UV. Strategies for disentangling multidimensional spectra, enhancing the resolution, and amplifying desired features will be developed. The optical response will be used to characterize small oligomers and their kinetics in the formation of fibrils. Discrimination by their size and structure is of fundamental importance for understanding the molecular factors that affect their formation. It has been suggested that the interactions of amyloidogenic polypeptides with the cell membrane can accelerate fibril formation and are involved in the toxicity of oligomers or protofibrils. Amyloid peptides aggregate on the lipid surface penetrate into membranes and alter their permeability, which may contribute to cell damage. The nonlinear optical probes developed in this program can directly monitor how the formation of fibrils on a membrane damages the bilayer's integrity. Interface-specific even-order optical techniques will be designed to study aggregates of amyloidogenic polypeptides on membranes and identify spectroscopic signatures of their toxicity. PUBLIC HEALTH RELEVANCE: The structure, kinetics, and aggregation mechanism of misfolded proteins which form amyloid fibrils and are associated with several human diseases will be investigated through their response to sequences of ultrashort infrared and UV optical pulses. Surface specific technique will be applied for probing the toxicity of fibrils on membranes. Simulation techniques for probing the binding, fluctuations, and motions of biomolecular complexes will be developed.